Echinocandins (caspofungin, micafungin, anidulafungin), targeting -1,3glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host's response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other -1,3-glucan synthase inhibitors (ibrexafungerp). KEYWORDS Aspergillus, anidulafungin, calcineurin, caspofungin, heat shock protein 90, ibrexafungerp, micafungin, paradoxical effect, rezafungin M olds of the genus Aspergillus (particularly, Aspergillus fumigatus) are the causal agents of invasive aspergillosis (IA), a life-threatening infection affecting immunocompromised hosts, such as hematological cancer or transplant patients. The current antifungal armamentarium for the treatment of IA is limited to three antifungal drug classes. Fungicidal drugs, such as the triazoles (e.g., voriconazole, posaconazole, or isavuconazole) and the polyenes (amphotericin B formulations) represent the firstchoice treatments, whereas the fungistatic echinocandins (caspofungin, anidulafungin, and micafungin) represent an alternative and are only marginally used as monotherapy (1, 2). However, use of echinocandins is gaining interest because of the emergence of acquired azole resistance in A. fumigatus isolates and the limitations related to drug interactions and/or toxicity with azoles and amphotericin B. The aim of this review is to discuss the role of the echinocandins in the treatment of IA, from the mechanistic point of view of drug-pathogen-host interactions to clinical application and perspectives. ECHINOCANDINS AGAINST ASPERGILLUSMechanisms of action. The echinocandin drugs are lipopeptides derived from fu...
Background Aspergillus spp. of section Usti (A. ustus) represent a rare cause of invasive aspergillosis (IA). This multicenter study describes the epidemiology and outcome of A. ustus infections. Methods Patients with A. ustus isolated from any clinical specimen were retrospectively identified in 22 hospitals from 8 countries. When available, isolates were sent for species identification (BenA/CaM sequencing) and antifungal susceptibility testing. Additional cases were identified by review of the literature. Cases were classified as proven/probable IA or no infection, according to standard international criteria. Results Clinical report forms were obtained for 90 patients, of whom 27 had proven/probable IA. An additional 45 cases were identified from literature review for a total of 72 cases of proven/probable IA. Hematopoietic cell and solid-organ transplant recipients accounted for 47% and 33% cases, respectively. Only 8% patients were neutropenic at time of diagnosis. Ongoing antimold prophylaxis was present in 47% of cases. Pulmonary IA represented 67% of cases. Primary or secondary extrapulmonary sites of infection were observed in 46% of cases, with skin being affected in 28% of cases. Multiple antifungal drugs were used (consecutively or in combination) in 67% of cases. The 24-week mortality rate was 58%. A. calidoustus was the most frequent causal agent. Minimal inhibitory concentrations encompassing 90% isolates (MIC90) were 1, 8, >16, and 4 µg/mL for amphotericin B, voriconazole, posaconazole, and isavuconazole, respectively. Conclusions Aspergillus ustus IA mainly occurred in nonneutropenic transplant patients and was frequently associated with extrapulmonary sites of infection. Mortality rate was high and optimal antifungal therapy remains to be defined.
A 22-year-old male with a typical history of pauci-symptomatic COVID-19 3 weeks earlier, confirmed by positive serology for SARS-CoV-2 (IgG), was admitted to the intensive care unit because of severe myocarditis with refractory cardiogenic shock that required extracorporeal life support. Due to a clinical presentation suggestive of Kawasaki-like disease with coronary aneurysm and severe systemic inflammation, intravenous immunoglobulins were administered in combination with tocilizumab. The initial clinical course was favourable with these treatments. However, the patient subsequently developed a severe mononeuritis multiplex leading to bilateral foot drop, which required intensive immunosuppressive therapy (corticosteroids, cyclophosphamide and rituximab). The clinical presentation meets the criteria for multisystem inflammatory syndrome associated with SARS-CoV-2, but includes very severe organ damages. Early recognition, a multidisciplinary approach and aggressive therapeutic intervention can lead to a favourable outcome.
Background Despite progress in diagnostic, prevention and treatment strategies, invasive mold infections (IMI) remain leading cause of mortality in allogeneic hematopoietic cell transplant recipients (allo-HCT-recipients). Methods We describe the incidence, risk factors, and mortality of allo-HCT-recipients with proven/probable IMI in a retrospective single-center 10-year (01.01.2010-01.01.2020) cohort study. Results Among 515 allo-HCT-recipients, 48 (9.3%) patients developed 51 proven/probable IMI: invasive aspergillosis (IA; 34/51, 67%), mucormycosis (9/51, 18%) and other molds (8/51, 15%). Overall 35/51 (68.6%) breakthrough-IMI (bIMI) were identified: 22/35 (62.8%) IA and 13/35 (37.1%) non-IA IMI. One-year IMI cumulative incidence was 7%: 4.9% and 2.1% for IA and non-IA IMI, respectively. Fourteen (29.2 %), 10 (20.8%), and 24 (50.0%) patients were diagnosed during the first 30, 31-180, and >180 days post-HCT, respectively. Risk factors for IMI included: prior allo-HCT (SHR:4.06, p=0.004) and ≥grade-2 acute graft-versus-host disease (aGvHD; SHR: 3.52, p<0.001). All-cause 1-year mortality was 33% (170/515): 48% (23/48) and 31.5% (147/467) for patients with and without IMI (p=0.02). Mortality predictors included: disease relapse (HR:7.47, p<0.001), aGvHD (HR:1.51, p=0.001), CMV-serology-positive recipients (HR:1.47, p=0.03), and IMI (HR:3.94, p<0.001). All-cause 12-week mortality for patients with IMI was 35.4% (17/48): 31.3% (10/32) for IA and 43.8% (7/16) for non-IA IMI (logrank 0.47). At 1-year post-IMI diagnosis, 70.8% (34/48) of patients were dead. Conclusions IA mortality has remained relatively unchanged during the last two decades. More than two thirds of allo-HCT-recipients with IMI die by 1-year post-IMI diagnosis. Dedicated intensified research efforts are required to further improve clinical outcomes.
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